Patent GB-1502312-A (GB)
Title: Quinolone derivatives
IPC: C07D215/26
Filed: 1975-03-20
Abstract: 1502312 Quinolone derivatives IMPERIAL CHEMICAL INDUSTRIES Ltd 19 Feb 1976 [20 March 1975 14 Oct 1975] 11644/75 and 42043/75 Heading C2C Novel compounds of the Formula I wherein A is a direct bond, or a C 1-4 -alkylene or C 2-4  alkenylene radical; R<SP>1</SP> is hydrogen or a halogen atom or a C 1-4 -alkyl radical; R<SP>2</SP> is hydrogen or a C 1-4 -alkyl radical; R<SP>3</SP> is a hydroxy, amino, hydroxylamino, C 1-6 -alkoxy or a phenoxy radical which may optionally bear one or two substituents selected from halogen atoms, nitro, trifluoromethyl, C 1-4 -alkyl and C 1-4 -alkoxy radicals; and wherein the benzene ring X may optionally bear 1 or 2 substituents selected from halogen atoms, C 1-6 -alkyl, C 1-4 - alkoxy, C 1-4 -alkylthio, trifluoromethyl, nitro, amino, C 1-4 -alkylamino, di(C 1-4 -alkyl)amino and C 2-4 -alkanoylamino radicals and from C 7-10 - aralkoxy radicals optionally substituted by a halogen atom, or may bear a single C 1-3 - alkylenedioxy radical; and wherein the ring Y is a phenyl radical which may optionally bear 1, 2 or 3 substituents selected from halogen atoms, C 1-6 -alkyl, C 1-4 -alkoxy, C 1-4 -alkylthio, C 1-4 -alkylsulphinyl, C 1-4 -alkylsulphonyl, C 1-4 - alkylamino, di(C 1-4 -alkyl)amino, nitro, cyano, trifluoromethyl and C 2-8 -alkoxyalkyl radicals and from C 6-10 -aryl radicals optionally substituted by 1 or 2 halogen atoms; or wherein the ring Y is a naphthyl or a monocyclic heterocyclic aromatic radical which may optionally bear 1 or 2 substituents selected from halogen atoms, C 1-4 -alkyl and C 1-4 -alkoxy radicals; or for those compounds of Formula I wherein benzene ring X and/or ring Y bear at least one amino, C 1-4 -alkylamino or di-(C 1-4 -alkyl)amino radical, or ring Y is a pyridyl radical, a pharmaceutically acceptable acid addition salt thereof; or for those compounds of Formula I wherein R<SP>3</SP> is a hydroxy radical a pharmaceutically acceptable base addition salt thereof, may be prepared (1) where R<SP>3</SP> is hydroxy, by hydrolysing and decarboxylating a compound II wherein R<SP>4</SP> is C 1-4 -alkoxy; (2) where R<SP>3</SP> is hydroxy, by hydrolysing and decarboxylating a compound IV (3) for a compound I wherein R<SP>3</SP> is C 1-4 -alkoxy and R 2  is C 1-4 -alkyl reacting a compound V where M is alkali metal with a C 1-4 -alkyl halide; (4) where the benzene ring X bears a nitro group, nitrating the corresponding compound I which is unsubstituted at X or bears one substituent which is not nitro; (5) where the benzene ring X bears at least one amino group, by reducing the nitro group(s) in the corresponding compound I wherein the benzene ring X bears at least one nitro group; (6) where R<SP>3</SP> is hydroxy, by reacting a compound VI wherein W is Li, Na or K, with dry carbon dioxide; (7) where A is C 1-4 -alkylene or C 2-4 - alkenylene, by reacting a compound VII wherein M is an alkali metal atom with a compound VIII wherein A is as defined above and Z is bromine or iodine when A is methylene or C 2-4 -alkenylene or iodine when A is C 2-4 -alkylene; (8) when R<SP>3</SP> is amino, hydroxylamino, C 1-4 -alkoxy, or a phenoxy radical optionally substituted with one or two substituents selected from halogen, nitro, trifluoromethyl, C 1-4  alkyl and C 1-4  alkoxy, by condensing a compound X or a reactive derivative of the carboxylic acid group with a compound R<SP>3</SP>H where R<SP>3</SP> is other than hydroxy; (a) where R<SP>3</SP> is hydroxy, by oxidizing a compound XI (10) where R<SP>3</SP> is hydroxy, hydrolysing a compound XIV wherein L is a radical COR<SP>5</SP> where R<SP>5</SP> is C 1-6 - alkoxy, aryloxy or aralkoxy or, when benzene ring X or ring Y bears a substituent other than a C 2-4  - alkanoylamino or cyano, respectively, wherein L is a cyano or carboxamido radical. Intermediates of the Formula II are prepared by reacting the appropriate 4-methyl quinoline with diethyl carbonate and strong base, optionally followed by alkylating to introduce an alkyl group at R<SP>2</SP>. Intermediates of the Formula IV are prepared by reacting the corresponding 4-methyl quinoline with diethyl oxalate in the presence of strong base. 1 - o - Chlorobenzyl - 4 - methyl - 6 - methoxy - 2- oxo-1,2-dihydroquinoline is prepared by reacting 2-chlorobenzaldehyde and 4-methoxyaniline followed by treatment with sodium borohydride to form N - (4 - methoxyphenyl) - 2 - chlorobenzylamine which on reaction with mercuric acetate and diketen followed by treatment with sulphuric acid yields the required compound. Numerous analogous intermediates are prepared by a similar method or by aralkylation of the corresponding 1-unsubstituted 4-methyl-2-oxo- 1,2-dihydroquinoline. 1 - p - Chlorophenyl - 6 - methoxy - 4 - methyl- 2-oxo-1,2-dihydroquinoline is prepared by reacting 4-methoxyanilide and 4-iodo-chlorobenzene in the presence of base and copper bronze, followed by treatment with ethanolic KOH to yield 4-chloro-4<SP>1</SP>-methoxydiphenylamine, which on treatment with mercuric sulphate and diketen gives N-acetoacetyl-4-chloro-4<SP>1</SP>-methoxydiphenylamine which on treatment with sulphuric acid cyclizes to the required compound. α - (1,2 - Dihydro - 2 - oxoquinol - 4 - yl) propionic acid is prepared by methylating 1,2- dihydro-4-methyl-2-oxoquinoline to form 4- ethyl-1,2-dihydro-2-oxoquinoline which with butyl lithium and then CO 2  yields the required acid. The 6-methyl compound is prepared by analogous process. 4 - (2 - Hydroxylethyl) - 6 - fluoro - 1 - (3,4,5- tribromobenzyl) - 1,2 - dihydro - 2 - oxoquinoline is prepared by forming the lithio derivative of 6 - fluoro - 4 - methyl - 1,2 - dihydro - 2 - oxoquinoline and reacting it with chloromethyl benzyl ether to form 4-(2-benzyloxyethyl)-6- fluoro - 1,2 - dihydro - 2 - oxo - quinoline which with sodium hydride and 3,4,5-tribromobenzylbromide yields 4 - (2 - benzyloxyethyl) - 6 - fluoro- 1 - (3,4,5 - tribromobenzyl) - 1,2 - dihydro - 2 - oxoquinoline which on hydrogenation yields the required compound. The 1-(3-chloro-4-bromobenzyl) and 1-(3,5-dichloro-4-bromobenzyl) analogues are prepared by similar processes. α - (6 - Nitro - 1,2 - dihydro 2 - oxo - quinol- 4-yl) propionic acid is prepared by nitration of α - (1,2 - dihydro - 2 - oxo - quinol - 4 - yl) propionic acid. 1 - (4 - Nitrobenzyl) - 1,2 - dihydro - 2 - oxoquinol-4-ylacetonitrile is prepared by reacting ethyl 1 - (4 - nitrobenzyl) - 1,2 - dihydro - 2 - oxoquinol-4-yl pyruvate (obtained as described for intermediates of the Formula IV) with hydroxylamine hydrochloride to yield ethyl 3-[1- (4 - nitrobenzyl) - 1,2 - dihydro - 2 - oxoquinol - 4- yl]-2-oximino pyruvate which on heating with sodium hydroxide solution and then acetic anhydride gives the required compound. Pharmaceutical compositions of the compounds I with the usual excipients may be administered orally, parenterally or rectally in the treatment of analgesia, inflammation, and/or in the inhibition of enzyme aldose reductose and/or enzyme prostaglandin synthetase. Compositions intended for treatment of the peripheral effects of diabetes may additionally contain known hypoglycaemic agents such as tolbutamide. Compositions intended as analgesics and/or anti-inflammatory agents may contain other known analgesics and anti-inflammatories such as paracetamol, codeine, acetyl salicylic acid chloroquine, phenylbutazone, D-penicillamine, indomethacin, ibuprofen, naproxan, ketoprofen or prednisolone or an uricosuric agent such as probeneciol.